A. Field of the Invention
The invention concerns insulin formulations for parenteral administration. These formulations can include stable monomer and dimeric forms of insulin, thereby speeding up the absorption rate of insulin into a subject's blood stream.
B. Description of Related Art
Patients with Type 1 diabetes produce little to no insulin, and thus the primary treatment for Type 1 diabetes is exogenous insulin therapy. Further, due to limitations of non-insulin treatments, many patients with Type 2 diabetes eventually require insulin therapy. Historically, insulin has been used for more than 90 years to treat diabetes. A typical regimen involves administering several injections of insulin each day: a long-acting basal insulin one or two times per day and a rapid-acting insulin at mealtimes. Although this treatment regimen is accepted as effective, it has limitations. First, patients generally dislike injecting themselves with insulin due to the inconvenience and pain of needles. As a result, patients tend not to comply adequately with the prescribed treatment regimens. More importantly, even when properly administered, no meal-time injectable insulin products adequately replicate the natural physiologic action of human insulin. In particular, the first-phase response in a non-diabetic consists of an insulin spike with the insulin level in the blood rising within several minutes of the entry of glucose into the blood from a meal. The insulin level in the blood will then peak between 30 and 60 minutes after the onset of action. In contrast, injected insulin enters the blood slowly, with the observed maximum concentration (Cmax) occurring 90 minutes or more following the injection of regular human insulin.
Various classes of therapeutic insulin and insulin analogues have been developed to achieve different pharmacokinetic (PK) profiles such as trading-off onset of action and time-to-peak plasma insulin with duration-of-action. A key improvement in insulin treatments was the introduction of rapid-acting insulin analogs, including HUMALOG®, NOVOLOG® and APIDRA®. However, even with these analogs, peak insulin levels typically occur ˜60 minutes following injection. The failure of currently marketed insulin products to adequately mimic the first-phase insulin release results in deficient insulin levels at the beginning of a meal and excessive insulin levels between meals, which can have the physiological effect of hyperglycemia early after meal onset and hypoglycemia late after meals. Both of these situations represent significant challenges to the promise of a closed-loop artificial pancreas technology in that complex algorithms are required to manage both latencies.
For diabetic patients treated with insulin, the primary route of administration of exogenous insulin is subcutaneous, and the primary parameters of the PK profile are dependent on subcutaneous absorption. A number of variables affect the absorption of subcutaneously injected insulin (e.g., blood flow, diffusion rates, and association state). When blood flow rates are sufficient, the rate-limiting factors for absorption of soluble insulin are (i) interstitial transport to the capillaries by diffusion and (ii) the restriction of transport over the capillary membrane both of which are governed by the size of the molecule (i.e., association state of insulin).
Typically, insulin formulations are aqueous-based. One reason for this is that the majority of the human body is made up of water, including blood plasma, which is an aqueous environment. Therefore, there is a natural tendency to administer a drug formulation that is compatible with the environment that the drug is intended to reach. While monomeric and dimeric insulin forms are more easily absorbed into the blood stream due to their smaller sizes when compared with the hexamer form of insulin, insulin is generally present in pharmaceutical compositions in the form of stabilized, zinc-bound hexamers. Monomeric insulin in aqueous solution is unstable, forming amyloid fibrils and degrading through water-mediated pathways. While the hexamer structure promotes stability in solution (pH 5-8), it also hinders diffusion and subsequent absorption. Further, the volume of the injection depot will also have an effect on diffusion, so that the larger the volume, the slower the diffusion rate. It is this combination of factors that is primarily responsible for the latency in onset of action and peak plasma insulin levels.
To prevent fibrillation and degradation of insulin in aqueous solution while also promoting subcutaneous absorption, insulin analogs have been developed where the amino acid sequence has been changed to reduce the propensity for self-association while preserving receptor-binding affinity. These classes of insulin are often referred to as “monomeric” insulin, but they actually exist as weakly associated hexamers. Absorption of such preparations will still be delayed because it is dependent on the diffusion and subsequent reduction in subcutaneous concentration required for the hexamer to dissociate to the dimer/monomer. Insulin analogs with equilibrium in favor of the monomeric state (e.g. the insulin analog Lispro) have shown more rapid absorption and a shorter duration of action. However, these analog molecules are less stable and more prone to irreversible aggregation under thermal and mechanical stress compared to hexameric insulin. Moreover, these aggregates decrease not only the dose of insulin available, but can also induce irritation or immune reactions in patients. Concerns also have emerged in experimental and epidemiological studies with respect to prolonged signaling of the receptor machinery and the induction of tumor proliferation by some newer insulin analogs. Despite their shortfalls, insulin analogs are costly—about twice as much as regular human insulin.